title: Dexamethasone increases αvβ3 integrin expression and affinity through a calcineurin/NFAT pathway.
abstract: The purpose of this study was to determine how dexamethasone (DEX) regulates the expression and activity of αvβ3 integrin. FACS analysis showed that DEX treatment induced expression of an activated αvβ3 integrin. Its expression remained high as long as DEX was present and continued following DEX removal. FACS analysis showed that the upregulation of αvβ3 integrin was the result of an increase in the expression of the β3 integrin subunit. By real time qPCR, DEX treatment induced a 6.2-fold increase (p<0.04) in β3 integrin mRNA by day 2 compared to control and remained elevated for 6days of treatment and then an additional 10days once the DEX was removed. The increase in β3 integrin mRNA levels required only 1day of DEX treatment to increase levels for 4days in the absence of DEX. In contrast, DEX did not alter β1 integrin mRNA or protein levels. The DEX-induced upregulation of β3 integrin mRNA was partly due to an increase in its half-life to 60.7h from 22.5h in control cultures (p<0.05) and could be inhibited by RU486 and cycloheximide, suggesting that DEX-induced de novo protein synthesis of an activation factor was needed. The calcineurin inhibitors cyclosporin A (CsA) and FK506 inhibited the DEX induced increase in β3 integrin mRNA. In summary, the DEX-induced increase in β3 integrin is a secondary glucocorticoid response that results in prolonged expression of αvβ3 integrin and the upregulation of the β3 integrin subunit through the calcineurin/NFAT pathway.
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Faralli
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Debjani
authors.initials: D
authors.lastname: Gagen
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Filla
authors.affiliation: Discipline of Anatomy and Pathology, The University of Adelaide, South Australia, Australia.
authors.forename: Tania N
authors.initials: TN
authors.lastname: Crotti
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Wisconsin, Madison, WI 53706, USA; Department of Ophthalmology & Visual Sciences, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Peters
mesh_terms: D019703:Calcineurin / Q000378:metabolism*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D015735:Mifepristone / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology; D014129:Trabecular Meshwork / Q000166:cytology
chemical_list: D039302:Integrin alphaVbeta3; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000431:Ethanol; D003907:Dexamethasone; D016572:Cyclosporine; D003513:Cycloheximide; D019703:Calcineurin; D016559:Tacrolimus
keywords: Calcineurin; Cytoskeleton; Glaucoma; Glucocorticoids; Integrin; Trabecular meshwork